Between about 5% and about 10% of the U.S. population suffers from chronic diarrhea for which an organic cause cannot be identified (Camilleri et al., 1977, Aliment Pharmacol Ther. 11:3-15; Talley et al., 1991, Gastroenterology 101:927-934). The diarrhea may be persistent or may alternate with periods of normal bowel habit or with periods of constipation. Chronic diarrhea which is not accompanied by abdominal. pain and which is not attributable to an organic cause is referred to as "functional diarrhea" (FD) or "chronic idiopathic diarrhea" (Drossman et al., 1997, Gastroenterology 112:2120-2137; Hasler et al., 1995, In: Textbook of Gastroenterology, 2nd ed., Yamada, Ed., J. B. Lippincott Co., Philadelphia, pp. 1832-1855; Camilleri et al., supra; Drossman et al., 1994, The functional Gastrointestinal disorders: Diagnosis, Pathophysiology, and Treatment, Degnon and Associates, McLean, Va.; Thompson et al., 1992, Gastroenterol. Intl. 5:75-91). Chronic diarrhea which is associated with abdominal pain and which is not attributable to an organic cause is referred to as "irritable bowel syndrome with a diarrhea predominance" (IBS; Hasler et al., supra; American Gastroenterological Association, 1997, Gastroenterol. 112:2118-2119; Drossman et al., 1997, Gastroenterol. 112:2120-2137; Camilleri et al., supra).
Postprandial urgency or postprandial accentuation of lower GI symptoms are common manifestations of both IBS and FD. Patients afflicted with either IBS or FD frequently experience an urgency to defecate after eating, and sometimes attribute this urgency to the ingestion of particular foods other than lactose. Furthermore, some of these patients associate exacerbation of their symptoms with emotional stress. These symptoms have led investigators of IBS and FD to believe that abnormal physiological factors, psychological factors, or both, may be associated with IBS and FD (Drossman et al., supra; Hasler et al., supra; Camilleri et al., supra; Drossman et al., supra; Drossman et al., supra; O'Brien et al., 1996, Gastroenterol. Clin. N. Am. 25:147-162; Bazzocchi et al., 1991, Gastroenterology 101:1298-1306; Choi et al., 1997, Am. J. Gastroenterol. 92:297-306; Aggarwal et al., 1994, Gastroenterology 106:945-950; Quigley, 1996, Gastroenterol. Clin. N. Am. 25:113-145; Schmidt et al., 1996, Scand. J. Gastroenterol. 31:581-589; Evans et al., 1996, Gastroenterology 110:393-404; Gorard et al., 1994, Gut 35:203; Kellow et al., 1990, Gastroenterology 98:1208; Whitehead, 1996, Gastroenterol. Clin. N. Am. 25:21-34). No effective therapy has been established for the chronic diarrhea or the postprandial urgency associated with either IBS or FD (Drossman et al., 1997, supra; Hasler et al., supra; Camilleri et al., supra; Drossman et al., 1994, supra; Thompson et al., supra; Klein, 1988 Gastroenterology 95:232-241).
IBS is believed to be a heterogeneous group of disorders, characterized by chronic lower gastrointestinal symptoms not associated with an identifiable organic cause. IBS is one of the most common chronic afflictions, not only in the U.S., but also in many other countries where it has been studied. It has been estimated that approximately between 9% and 22% of the U.S. population is afflicted with IBS. Most people afflicted with IBS, probably over 70% of such people, do not seek a physician's care. Nonetheless, people afflicted with IBS miss about 3 times as many work days as people not so afflicted. Furthermore, IBS sufferers account for about 12% of primary care practice and about 28% of gastroenterological practice, and constitute nearly half of the outpatients who are referred to gastroenterologists.
The "spastic" variety of IBS, which is characterized by abdominal pain and constipation, is believed to be somewhat more common than IBS associated with chronic diarrhea and postprandial urgency. However, as noted above, the "diarrhea predominance" variety is also common. Because the definition and diagnosis of IBS have been somewhat controversial, attempts have been made in recent years to reach some consensus regarding the definition of IBS and other functional or non-organic GI disorders, and the clinical criteria for their diagnosis (Drossman et al., supra; Hasler et al., supra; Camilleri et al., supra; Drossman et al., supra; Thompson et al., 1989, Gastroenterol. Intl. 2:92-95; Manning et al., 1978, Br. Med. J. 2:653-654 and Thompson et al., supra). According to the so-called "Rome criteria," patients afflicted with chronic diarrhea not attributable to an organic cause and not accompanied by significant abdominal pain are classified as having FD, and those patients afflicted with chronic diarrhea not attributable to an organic cause and accompanied by significant abdominal discomfort are classified as having IBS with diarrhea predominance (Drossman et al., supra; Hasler et al.,supra; Camilleri et al., supra; Drossman et al., supra; Thompson et al., supra; Manning et al., supra).
Several possible etiologies and pathophysiological mechanisms have been suggested for IBS and FD, including a psychophysiological or psychosomatic mechanism, a primary motor or dysmotility mechanism such as an exaggerated gastrocolic reflex due to some neural, endocrine, or muscle dysfuinction, or some combination thereof, and a visceral hypersensitivity mechanism (Drossman et al., 1997, supra; Hasler et al., supra; Camilleri et al., supra; Drossman et al., 1994, supra; O'Brien et al., supra; Bazzocchi et al., supra; Choi et al., supra; Aggarwal et al., supra; Quigley, et al., supra; Schmidt et al., supra; Evans et al., supra; Gorard et al., supra; Kellow et al., supra; Whitehead et al., supra; Suolund et al., 1987, Scand. J. Gastroenterol. 130(Suppl):15-20). Furthermore, certain patients previously thought to have IBS have been discovered to have identifiable GI disorders, such as lactase deficiency, collagenous colitis, and lymphocytic (microscopic) colitis (Weser et al., 1965, N. Eng. J. Med. 273: 1070-1075; Maxson et al., 1994, Med. Clin. N. Am. 78: 1259-1273; Lindstrom, 1976, Pathol. Err. 11:87-89 and Read et al., 1980, Gastroenterology 78:264-271). Today, before a diagnosis of IBS or FD is made, these "organic" causes of chronic diarrhea should be excluded.
It has been suggested that some IBS or FD patients actually have cholereic diarrhea due to a colonic or small intestinal hypersensitivity to bile acids or an inapparent malabsorption of bile acids (Drossman et al., 1997, Gastroenterology 112:2120-2137; Hasler et al., 1995, In: Textbook of Gastroenterology, 2 nd ed., Yamada, Ed., J. B. Lippincott Co., Philadelphia, pp. 1832-1855; Camilleri et al., supra; Drossman et al., 1994, The functional Gastrointestinal disorders: Diagnosis, Pathophysiology, and Treatment, Degnon and Associates, McLean, Va.; Taylor et al., 1980, Gut 21:853; Oddson et al., 1978, Scand. J. Gastroenterol. 13:409-416; Thaysen et al., 1976, Gut 17:965-970; Merrick et al., 1985, Br. Med. J. 290:665-668; Schiller et al., 1987, Gastroenterology 92:151-160). However, an apparent response to administration of cholestyramine, which is a constipating agent that was administered to IBS patients in certain of these studies, should not necessarily establish the presence of such a disorder. In addition, the role that dietary sorbitol, fructose, and food allergens may have in the development of lower GI symptoms in some patients remains unclear (Camilleri et al., supra; Nanda et al., 1989, Gut 30:1099-1104; Hyams, 1983, Gastroenterology 84:30-33; Rumessen et al., 1988, Gastroenterology 95:694-700; Nelis et al., 1990, Gastroenterology 98:A194).
Collagenous colitis is a condition characterized by chronic diarrhea and abnormalities of the colonic mucosa. Colonoscopy of patients afflicted with collagenous colitis usually reveals no apparent abnormality. However, biopsies of the colonic mucosa of such patients, which are usually obtained at the time of colonoscopy or sigmoidoscopy reveals inflammation of colon tissue and the presence of an abnormal collagen layer below the surface epithelium.
Ulcerative colitis is an inflammatory disease of the colon characterized by chronic diarrhea which is often bloody. Ulcerative colitis may affect only a portion of the colon or it may affect the entire length of the colon, in which case the disease is designated `pan-ulcerative colitis.`
Giardiasis is an example of an infectious disease characterized by diarrhea, which is often chronic and which is caused by a parasite (the protozoan Giardia lamblia). Other parasites and infectious agents, such as bacteria and viruses, cause diarrhea which may be acute or chronic.
Many previous treatments for chronic diarrhea in patients afflicted with IBS or FD have proven to have limited, if any, efficacy. These previous treatments include restrictive diets, administration of fiber, loperamide, diphenoxylate, other opiates, anticholinergics, antispasmodics, cholestyramine, tricylic and serotonin reuptake inhibitor antidepressants, sedatives, and psychological therapy. Patients afflicted with IBS and FD have been treated with limited success by administering anticholinergic agents to reduce intestinal motility in those patients. It was presumed that these anticholinergic agents achieved their effect by inhibiting stimulant cholinergic innervation pathways of the intestines, and not owing to any capacity of such agents to inhibit gastric secretion.
Clearly, therefore, a significant unmet need remains for an efficacious treatment of patients afflicted with lower GI disorders, including alleviation of lower GI symptoms, such as chronic diarrhea and postprandial urgency, which are associated with lower GI disorders such as IBS or FD.